The role of chest X-ray in the diagnosis of neonatal respiratory distress syndrome: a systematic review concerning low-resource birth scenarios

ABSTRACT Background Access to diagnostic tools like chest radiography (CXR) is challenging in resource-limited areas. Despite reduced reliance on CXR due to the need for quick clinical decisions, its usage remains prevalent in the approach to neonatal respiratory distress syndrome (NRDS). Objectives To assess CXR’s role in diagnosing and grading NRDS severity compared to current clinical features and laboratory standards. Methods A review of studies with NRDS diagnostic criteria was conducted across six databases (MEDLINE, EMBASE, BVS, Scopus-Elsevier, Web of Science, Cochrane) up to 3 March 2023. Independent reviewers selected studies, with discrepancies resolved by a senior reviewer. Data were organised into descriptive tables to highlight the use of CXR and clinical indicators of NRDS. Results Out of 1,686 studies screened, 23 were selected, involving a total of 2,245 newborns. All selected studies used CXR to diagnose NRDS, and 21 (91%) applied it to assess disease severity. While seven reports (30%) indicated that CXR is irreplaceable by other diagnostic tools for NRDS diagnosis, 10 studies (43%) found that alternative methods surpassed CXR in several respects, such as severity assessment, monitoring progress, predicting the need for surfactant therapy, foreseeing Continuous Positive Airway Pressure failure, anticipating intubation requirements, and aiding in differential diagnosis. Conclusion CXR remains an important diagnostic tool for NRDS. Despite its continued use in scientific reports, the findings suggest that the study’s outcomes may not fully reflect the current global clinical practices, especially in low-resource settings where the early NRDS approach remains a challenge for neonatal survival. Trial registration: PROSPERO number CRD42022336480.


Introduction
Neonatal respiratory distress syndrome (NRDS) is a common neonatal disease and the leading cause of death in children worldwide, accounting for approximately 16% of all deaths below five years of age and 35% of deaths among newborns [1].Socioeconomic status is an important health determinant across maternal and child health outcomes [2] and the majority of neonatal deaths occur in low-and middle-income countries (LMIC) [3].NRDS is caused by the immature lung structure and function.The lack of pulmonary surfactant, due to either inadequate production or surfactant inactivation in the context of immature lungs, affects the gas exchange leading to acidosis and hypoxemia [4].The natural course of NRDS is the onset of symptoms at the time of birth with progressive hypoxia and respiratory failure if not treated in time.Therefore, prompt diagnosis is required to ensure an effective treatment and reduce neonatal death rate [5].
Since the definition of NRDS is inaccurate, the current diagnostic includes the assessment of medical records for perinatal risk factors identification, clinical symptoms, radiographic findings, and blood gas analysis with evidence of hypercapnia and hypoxemia [6].The clinical presentation consists of respiratory symptoms with increased work of breathing, including tachypnea, nasal flaring, grunting, retractions and use of accessory muscles, cyanosis, with decreased air entry on auscultation.The pathognomonic findings on radiography include homogeneous lung disease with diffuse atelectasis, a ground-glass reticulo-granular appearance, with air bronchograms and low lung volumes [7].
In the management of neonatal lung diseases that require NICU admission, chest x-ray (CXR) is the most used medical imaging for the initial diagnosis of major clinical changes in the respiratory profile and is the standard procedure to determine the placement of probes, tubes and catheters [8].However, social inequalities between high-income countries (HIC) and LMIC are worrying in terms of health and well-being.Lack of access to high-cost technologies and professionals trained to perform diagnostic imaging is part of the challenge in offering due care for preterm newborns.
Equal access to healthcare ensures timely and effective diagnoses, facilitating appropriate care, such as allowing adequate time for transferring newborns to referral centres.While there's a trend in clinical practice, as reported in guidelines, to decrease CXR use, it often involves substituting with even less accessible exams for low-resource populations.Disparities contribute to the increasing global burden of disease and mortality, with infant mortality in the first day of life being 30 times higher in LMIC [9,10].
Furthermore, evidence supports that ionising radiation causes cellular damage, and that there is a linear increase in lifetime cancer risk, even at low doses of exposure.Neonatal organs which are not fully developed and are more sensitive to CXR, repeated examinations can cause and amplify radiation damage.The risk of the effects of ionising radiation is higher the younger the child is, thus dose reduction is a goal in the field of neonatology [5].
Clinical guidelines aim to minimise exposure to ionising radiation, furthermore CXR is not always available in low-income settings.However, no review has demonstrated whether radiography is necessary for confirming diagnosis [11].Investigating the importance of CXR in assessing and diagnosing NRDS could improve treatment in resource-limited facilities.Clarifying the need for CXR versus the sufficiency of clinical features could guide future approaches.Identification of the purpose of the CRX in the diagnosis of NRDS should be evaluated as mandatory use, in conjunction with other criteria, for differential diagnosis, to classify the severity of NRDS, to guide treatment or for other reasons.
Therefore, the review aims to determine the necessity of CXR for diagnosing and classifying the severity of NRDS compared to clinical features and laboratory standards.

Eligibility criteria
The systematic review had the International Prospective Registry of Systematic Reviews under PROSPERO number: CRD42022336480.The research protocol followed the recommendations of the PRISMA Statement [12].To structure the research question about the role of CXR in diagnosing and classifying the severity of NRDS, the acronym PECOS was used.Therefore, in the search for evidence, infants, newborns were considered for (P) Population; for (E) Exposure the CXR; as (C) Comparator the standards of clinical features to establish or assist in the diagnosis of NRDS.Current clinical features, such as evaluation of signs and symptoms, as well as laboratory tests, cited as supporting the diagnosis; as (O) Outcomes the NRDS diagnosis (primary) and NRDS severity classification (secondary); and (S) Study the observational and interventional studies.This research employed two independent pairs of reviewers and a third senior investigator to resolve any discrepancies at each step throughout the entire process.
Studies based on the newborn population with defined criteria for diagnosing NRDS, from the earliest record to the 3rd of March 2023, were included.The language was restricted to English, Portuguese, Spanish, and French.It was considered studies investigating the criteria used to diagnose NRDS and the mandatory use or not of the CXR.
Studies that did not refer to research questions, in addition to incomplete articles, abstracts, review articles, editorials, books, scholar papers, dissertations and theses were excluded.

Information sources and search strategy
The search was conducted on PubMed (MEDLINE), EMBASE, BVS, Scopus-Elsevier, Web of Science, and Cochrane.Searching process was conducted through descriptors and correlates found in the Medical Subject Heading (MeSH) and descriptors in Health Sciences (DeCS), according to the search strategy of each database.
Complete search strategy, adopting specific descriptors linked to Boolean operators, was ('Infant, Newborn' OR Neonate OR Newborn OR 'Newborn Infant') AND (Radiography OR 'Diagnostic X Ray' OR "Diagnostic X Ray Radiology'' OR 'Diagnostic X-Ray' OR 'Diagnostic X-Ray Radiology' OR 'Radiology, Diagnostic X Ray' OR 'X Ray Radiology, Diagnostic' OR 'X Ray, Diagnostic' OR 'X-Ray Radiology, Diagnostic' OR 'X-Ray, Diagnostic' OR 'X-Rays, Diagnostic') AND (Lung OR Chest) AND ('Respiratory Distress Syndrome, Newborn' OR 'Hyaline Membrane Disease' OR 'Neonatal Respiratory Distress Syndrome' OR 'Disease, Hyaline Membrane').Whenever possible, the following filters were used: type of studies: only in humans; and methodological design: clinical trials, cohort, and clinical practice guidelines; limited to medical and health subject area; limited to thorax Radiography.Supplementary file 1 provides the full line by line search strategy as run in each database with the sequence of terms that were used to search on interfaces.
The data search, screening and inclusion procedures are illustrated in Figure 1.In the first phase of the search, 1,686 studies were retrieved.Among these, 762 were sourced from the PubMed database, 635 from Scopus, 1 from Web of Science, 25 from Cochrane, 42 from BVS, and 221 from Embase.After a comprehensive analysis, 23 studies out of 1686 were chosen, involving a total of 2,245 newborns.

Selection and data collection process
References retrieved from search strategies were exported to StArt ® (v.3.3.Beta 03) file [13], and duplicates were removed.Following this procedure, studies were screened based on titles and abstracts, and subsequently, in their full-text versions, according to the inclusion criteria outlined above.
The final selection of included studies was carried out for qualitative and quantitative analysis.Subsequently, data were extracted and the characteristics of the included studies were broken down: authors, year of publication, study period, country, study design, population characteristics, main objective, clues for diagnosis with clinical evaluation, such as oximetry, frequency and signs of respiratory effort, or by laboratory tests and CXR.Any other data of interest that reply to the scientific question was taken into account.

Data items (outcomes)
Investigations into the rate of NRDS and the importance of CXR in the assessment of NRDS were performed in each study.The main use of this exam was marked as 1) mandatory criterion for the NRDS Figure 1.Flowchart with detailed research data for the identified studies for each phase, according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) [12].
diagnosis conjoining clinical features, 2) to complete the clinical features, but not as a mandatory for diagnosis, 3) to assess other diseases (differential diagnosis of pulmonary conditions), 4) to classify the severity of NRDS, 5) guide the surfactant administration, or 6) for any other reason, such as verifying the correct placement of devices as an endotracheal tube.The main patterns in the CXR findings to characterise the NRDS were described as well as the criteria considered for differential diagnosis.When available, the time when the CXR was taken was presented.In studies with a control group, the best diagnostic accuracy was described.When classifying the severity of NRDS, the classification method/system was detailed.When used to guide exogenous surfactant replacement, the timing and patterns observed on CXR were revealed.

Study risk of bias assessment
For the risk of bias in randomised trials, the revised RoB 2.0 tool was used.The methodological quality of selected observational studies was evaluated by the Newcastle-Ottawa Scale (NOS) adjusted for the context of the review [14], detailed in Supplementary file 2.

Synthesis methods
The primary endpoint of the study was the diagnosis of NRDS, and the effect measures were the number of studies that did or did not recommend CXR as a diagnostic criterion for NRDS.Furthermore, the synthesis of the diagnostic of NRDS with and without CXR support was compared.The secondary outcome was the utilisation of CXR as a criterion for NRDS severity classification.In addition, elements of CXR analysis considered relevant for such classification were extracted and a summary of the topic was provided.Differences in diagnostic rates between CXR and other diagnostic methods, such as clinical features, were summarised, as well as divergences in severity rating rates.
After extraction, the data was summarised in tables.Characteristics of the studies, epidemiological characteristics of the participants, year, author, and outcomes were identified and described.Subgroups of analysis were planned, when available, on the basis of socioeconomic inequalities (LMIC vs. HIC); grades of prematurity (extremely preterm vs. very preterm vs. moderate to late preterm); birth weight categories (low birth weight vs normal birth weight vs high birth weight); and arrangements considering the date of publication.

Results
The general characterisation of eligible articles is presented in Table 1.Among the 23 articles included, the publication years ranged from 1987 to 2022.The study designs varied, with 9 (39%) being cohort studies, 5 (22%) case-control studies, 8 (35%) crosssectional studies, and 1 (4%) clinical trial.The sample sizes in these studies ranged from 33 to 235 newborns.Regarding the target population, there were variations among the studies based on the gestational age included.
Table 2 provides an overview of the characterisation of CXR usage and the clinical features associated with NRDS.It's worth noting that there was no consensus regarding the exact timing of CXR exposure in the included studies.While all studies reported the use of the first CXR for diagnosing NRDS, the timing of this CXR varied.Specifically, in 12 (52%) of the studies, the CXR was conducted between 2 and 24 hours of life.Four (17%) did not define a specific timing, four (17%) considered the timing after admission to the NICU, two (9%) specified the CXR being conducted 2 hours after CPAP initiation, and one (4%) reported that the CXR was done before surfactant administration.

Primary endpoint
Despite the differing objectives of each included study, they consistently utilised CXR as a reference for diagnosing NRDS.In summary, some reports emphasised that CXR cannot be replaced by other tools for diagnosing NRDS [17,22,23,25,26,29,30].Furthermore, the first CXR taken had the greatest impact on neonatal care [16,21].There was a consensus among health professionals in diagnosing with the exam, including agreement between clinicians and radiologists [16].Additionally, there was agreement between CXR and other exams, such as ultrasound (US), for NRDS diagnosis [35,37].However, while CXR has the ability to support the prediction of surfactant administration [15], it can be replaced by other tools for this purpose [27,[31][32][33][34].

Secondary endpoint
The importance of CXR in classifying the severity of NRDS was emphasised in 21 (91%) of the studies.The classification systems varied, typically consisting of either three or four classes, often referred to as stages or grades.The main characteristics observed on CXR progressively worsen with higher NRDS severity classifications.These principal patterns include a fine ground glass appearance with reduced lung volume and an air-bronchogram within the cardiac shadow.Selected studies reported agreement between CXR and other exams (e.g. the US) for NRDS severity classification [18,20,28], while others suggested that CXR was surpassed by alternative methods [31].In terms of the standards of clinical features for establishing or assisting the diagnosis of NRDS, three articles (13%) did not consider it at all.Additionally, CXR had other applications in the included studies, including 6 (26%) for differential diagnosis, 6 (26%) for surveillance and follow-up treatment, 6 (26%) to guide surfactant administration, 3 (13%) to predict CPAP failure, and 3 (13%) to detect complications of NRDS.To support the diagnostic decision, 9 (39%) studies referred to a protocol or guideline, while 14 (61%) did not mention any specific guidelines or protocols.When compared, other diagnostic tools were superior to CXR in various roles, including predicting CPAP failure [31], predicting the need for intubation [19], making a differential diagnosis [34], and for NRDS surveillance [34].
The quality of the selected studies was assessed using the NOS Scale, with a full description provided in the supplementary file 3, and the RoB 2 tool.The RoB 2.0 tool was employed to assess the risk of bias in the randomised trial, with the following judgements for each domain: Overall, the majority of studies were of good to high quality, with 9 classified as high quality, 9 as good quality, according to NOS, and 2 rated as poor quality according to NOS and ROB2 each.A causal inference is constrained by risk of bias in some studies, the main concerns being the lack of adjustment for key potential confounders such as gestational age and birth weight [16,19,25,27,31,34,35]; assessment of outcome due to an inappropriate or not-described statistical approach for comparing NDRS diagnoses techniques (CXR and other) [16,17,25]; the lack of representativeness of the NRDS cases [18,20,23,24]; or lack of independent blind assessment (e.g diagnosis based on CXR and medical records by independent professionals or diagnosis based on CXR blinded to the researcher [21,25,32,34,37].

Discussion
This review evaluated the importance of CXR for the diagnosis and classification of NRDS severity.Among the 23 studies included, all reported CXR as a standard diagnostic tool.Additionally, 21 studies used it to classify NRDS severity.There were other uses related to imaging as well: six studies for differential diagnosis, six for surveillance, six to guide surfactant administration, three to detect NRDS complications, and three to predict CPAP failure.It's important to interpret these findings with caution since CXR was one of the inclusion criteria for this review.
Early diagnosis of NRDS, necessary to anticipate therapeutic measures, depends on a combination of clinical signs and symptoms, laboratory analyses, and CXR [38].While CXR has traditionally been considered the standard diagnostic tool for NRDS, in clinical practice, it may not be as useful for making the final diagnosis in certain circumstances.For instance, in cases of congenital pneumonia and severe NRDS, where similarities are found in CXR findings [17,25].Moreover, the guidelines recommend making a decision on surfactant administration based on clinical features, irrespective of CXR results [39].Furthermore, in situations where CXR is not feasible, especially in resource-constrained environments or to minimise ionising radiation exposure, clinical classification of severity may serve as an alternative, as it demonstrates correlation with radiological findings [38].This review did not encompass scenarios with limited resources, considering the socio-economic classification of the majority of selected articles.Future studies focused on obtaining answers in LMIC scenarios may provide specific evidence on this issue.
Chronologically, early studies demonstrated the role of CXR in classifying the severity and prognosis of NRDS, which aided in identifying infants requiring surfactant administration.It also facilitated treatment surveillance, allowing assessment before and after surfactant administration [15].However, a significant development in neonatology, particularly the early use of nasal CPAP since the 1990s, led to a shift in NRDS severity classification towards clinical determination [40].This change has resulted in reduced reliance on mechanical ventilation and surfactant use [39].
Among the selected studies, the significance of the earliest CXR in the care of newborns was evident.It demonstrated the ability to detect most lung diseases in the first hours of life [16].At one point, conducting an initial CXR was deemed a standard practice for diagnosing NRDS and for surveillance, particularly in extremely premature infants [15].Additionally, it was considered essential for differentiating respiratory disorders in newborns and for precise placement of catheters, probes, and endotracheal tubes [17].Follow-up images also served to monitor therapeutic effects and reduce morbidities like bronchopulmonary dysplasia (BPD) by minimising mechanical ventilation [38].However, repeated examinations posed risks to neonates due to ionising radiation exposure [17].As a result, researchers explored alternative techniques to replace CXR due to these risks.Three studies compared CXR with laboratory tests, including expression levels of cysteine aspartic protease-3 (capase-3) and B-cell lymphoma gene-2 (Bcl-2) [28], levels of brain natriuretic peptide (BNP) [18], and surfactant protein B (SP-B) expression [20], while 16 studies focused on the use of US [17,19,[22][23][24][25][26][27][29][30][31][32][33][34][35]37].While alternative diagnostic methods were investigated to complement or even surpass CXR's functions, the recommendations for its use began to be questioned over time.Our interpretation of this outcome underscores the enduring importance of clinical features over time, regardless of diagnostic tools.
In summarising the selected articles for this review, several investigations have emphasised the significance of early CXR during the course of neonatal respiratory distress syndrome (NRDS).Kurl et al. (1997) highlighted its impact in detecting critical conditions, such as pneumothoraces, before severe clinical deterioration occurs [16].Additionally, Bober et al. (2006) found it to be essential for the differential diagnosis of respiratory disorders in neonates [17].Furthermore, Tagliaferro et al. (2015) explored its potential in predicting CPAP failure within the first 72 hours of life, particularly in ELBW infants.While one study confirmed this potential [21], Raimondi (2014) also demonstrated that a non-ionising examination could potentially replace the need for CXR [19].

Strength and limitations of the review
The main contribution of this study was to emphasise the evolving use of complementary exams over time and the need to review the role of CXR in clinical practices.Despite technological advancements in neonatology, the CXR associated with clinical features remains the standard reference for diagnosing NRDS.
The results found in this review have limitations, as the studies evaluated did not address the risks and benefits of the systematic use of CXR, nor did they consider the implications of repeated exams for NRDS follow-up.We believe that there is a future agenda to reevaluate recommendations for the mandatory use of CXR whenever NRDS is suspected.Providing guidelines on when to use this tool could be valuable in guiding clinical practice, with the dual aim of minimising unnecessary radiation exposure and ensuring timely access to essential clinical information.Furthermore, although the risk of bias in most studies was low, it's important to note that the primary objectives of the selected articles did not revolve around comparing clinical and radiological methods for diagnosing NRDS or assessing its severity.Some of these studies aimed to compare CXR with other diagnostic tools, such as the US, for NRDS diagnosis, or to predict the use of surfactant, among other objectives.The significant variation in study objectives was a limiting factor in interpreting the results for clinical practice.

Conclusion
The role of CXR has evolved over time, from NRDS diagnosis and severity classification to differential diagnosis and surfactant treatment surveillance.Still, CXR is considered a standard tool for confirmatory NRDS diagnosis.Although new complementary exams to assess NRDS in newborns have been studied over the years, the clinical features kept the importance for establishing or assisting the diagnosis of NRDS.
The scarcity of studies dedicated to assessing the relevance of CXR for NRDS evaluation has left it uncertain whether CXR assessment is mandatory for the diagnosis and severity classification of NRDS.Despite its continued use in scientific reports, the findings suggest that the study's outcomes may not fully reflect the current global clinical practices, especially in low-resource settings where the early NRDS approach remains a challenge for neonatal survival.

Table 1 .
General characterisation of eligible articles.

Table 2 .
Characterisation of CXR use and clinical features associated with NRDS.